Targeting the alternative pathway of complement to treat age-related macular degeneration Abstract Age-related macular degeneration (AMD) is the leading cause of vision loss in the developed world in people over 50 and is a priority research area for the National Eye Institute. It is a progressive, degenerative disease that causes loss of the central vision due to destruction of the part of the retina called the macula. An estimated 10 million Americans are affected by AMD and approximately 2 million suffer from advanced AMD. There is a significant impact on patients' quality-of-life as the ability to drive, read and care for oneself are impaired. There are limited treatment options available for AMD, and they primarily target one of the advanced forms of AMD called wet AMD. The pharmaceutical treatments are all anti-angiogenic drugs targeting the protein vascular endothelial growth factor (VEGF). These drugs do not target the other advanced form of AMD, geographic atrophy (GA). Additionally, these drugs are not effective against the early stages of AMD. Developing a therapeutic that targets a different pathway involved in AMD would provide treatment options for early AMD, GA and wet AMD and potentially block progression to late AMD, thus preventing vision loss. The complement system is a branch of the immune system that serves to rapidly respond to invading pathogens or tissue injury. It includes a potent amplification loop that can lead to host tissue damage if complement is not adequately regulated. Overactivation of the complement system has been implicated in the pathogenesis of AMD. Genetic and functional studies have demonstrated that alterations in proteins in one of the activation pathways of complement, the alternative pathway, result in excessive complement activation, which is seen early in the disease process. Therefore, the complement system is an attractive pharmacologic target. Development of complement inhibitors to date has primarily focused on biologics. Serion is developing a peptide inhibitor of an essential serine protease of the alternative pathway with the long-term goal of identifying a drug that will prevent progression to late stage AMD. In this SBIR Phase I, we will test the hypothesis that a peptide inhibitor can be designed to prevent complement activation via the alternative pathway. To test this, a two-pronged approach to modify the peptide will be employed. In Aim 1, the guidance system (peptide sequence) and warhead (serine trapping group) will be modified to identify the essential amino acids for target specificity and potency. The compound(s) optimized in this Phase I will then undergo efficacy studies in a mouse model of AMD, IND-enabling studies such as acute toxicity and pharmacokinetics and pharmacodynamics in Phase II.